Anticoccidial activities of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine and other alpha 2 adrenergic agonists

Abstract

Activity against the coccidial pathogen Eimeria tenella in chickens has been discovered among a2 adrenergic agonists. The clonidine analog 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine was active in feed at 7.5 ppm, a concentration similar to the use levels of potent commercial agents, e.g., maduramicin. Additional a2 agonists were also found to have anticoccidial activity, for example, the catecholamine nordefrin, which is chemically unrelated to clonidine. However, al agonists and a antagonists were inactive. These observations imply that anticoccidial effects reflect involvement of a receptor with the characteristics of the vertebrate a2 adrenoceptor. a2 agonists that permeate the blood-brain barrier (like clonidine) inhibit feed intake at efficacious levels, whereas those that are restricted to the peripheral compartment (such as catecholamines) do not inhibit feed intake as much. Hence, anticoccidial efficacy may be a peripheral adrenergic effect whereas depression of feed intake is likely centrally mediated.Coccidiosis, an intestinal disease of great economic importance in the poultry industry, is caused by intracellular protozoan parasites of the genus Eimeria. Although more than 20 different anticoccidial agents have been commercialized, the current drugs of choice belong to a single class: the polyether ionophores. Because of the ever-present threat that coccidia will develop resistance to these agents, there is a continuing need to discover new classes of anticoccidial agents.In the course of evaluating compounds from our files, 7-bromo-N-(2-imidazolidinylidene)-lH-indazol-6-amine (compound I) proved to be active against Eimeria tenella infections in chickens; however, it led to low weight gains. Compound I was prepared originally as a clonidine analog. Clonidine produces a variety of effects, owing to its a2 adrenergic agonist activities, and has found clinical use as an antihypertensive agent (7). Compound I also shows a2 agonist properties (3). We therefore explored the possibility that the observed anticoccidial activity was dependent upon stimulation of a2 adrenoceptors. If this were the case, it would follow that other a2 agonists, those structurally unrelated to clonidine, would show this effect. Conversely, a1 adrenergic agonists and a antagonists should be inactive. To test this hypothesis, we evaluated the anticoccidial activities of a variety of a adrenergic agents.We discovered that (i) among a adrenergic agents, anticoccidial activity is associated only with a2 agonists; (ii) a2 agonists other than clonidine analogs are also effective; and (iii) a2 agonists that cannot cross the blood-brain barrier, such as catecholamines, are effective and at the same time not as weight suppressive.MATERIALS AND METHODS General. Melting points are uncorrected. Yields were not maximized. All compounds had 'H nuclear magnetic resonance spectra that were consistent with their assigned structures. The following agents were either purchased from * Corresponding author. 7-Bromo-lH-indazol-6-amine. A solu...

Further investigation of anticoccidial activity of 7-bromo-N-(2-imidazolidinylidene)-1H-indazol-6-amine

“…The medicinal importance of clonidine stems from its ability to stimulate central a2 receptors to lower blood pressure. Evidence for a link between a2 agonist and anticoccidial actions is presented in the accompanying report (13) and was further supported by the present studies. Compound I and clonidine were both demonstrated to bind to a2 adrenergic receptors and act as agonists.…”

“…The accompanying report (13) documents the virtually complete control of E. tenella lesions achieved by compound I at 15 ppm, with significant activity at doses as low as 3.75 ppm. To confirm that this improvement in visible lesions reflects a genuine reduction in parasite numbers, histopathologic examinations of ceca from infected and uninfected chicks were conducted with and without medication with compound I (Fig.…”

“…In a program to discover novel anticoccidial agents, potent anticoccidial activity was found for the clonidine analog compound 1 (13). This compound showed virtually complete control of lesions caused by E. tenella at a dose of 15 ppm and retained significant activity down to 3.75 ppm.…”

“…Anticoccidial efficacy testing was conducted as described in the accompanying report (13). Cecal tissue samples from some treatments were fixed, embedded, and sectioned for histological examination.…”

“…The evidence suggests that we have observed a new Discovery of anticoccidial activity among a2 adrenergic agonists is described in the accompanying report (13). In the work discussed here, we focused on 7-bromo-N-(2-imidazolidinylidene)-lH-indazol-6-amine (compound I), the most potent anticoccidial agent of its class, and further explored the association between anticoccidial and adrenergic activities.…”